Vitamin b12 compositions

ABSTRACT

This disclosure provides compositions of vitamin B 12 , and methods of treatment or amelioration of a disease associated with vitamin B 12  deficiency. The composition can take the form of a solid, semi-solid, gummy, or chewable lozenge. The composition can also take the form of a troche, a candy, a wafer, an orally disintegrating tablet, a sublingual tablet, a buccal tablet, a buccal patch, an oral dissolvable film, an aerosol or spray, a lip balm, and chewing gum.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of copending U.S. applicationSer. No. 11/219,794 filed on Sep. 7, 2005, herein incorporated byreference in its entirety.

FIELD OF INVENTION

The present invention provides improved vitamin B₁₂ compositionscontaining a mixture of vitamin B₁₂ analogues in effective amounts forenhanced delivery via the mucosal membranes, such as the mouth, nose,etc., to ameliorate any condition associated with vitamin B₁₂ deficiencyin a human.

BACKGROUND OF THE INVENTION

Vitamin B₁₂, otherwise known as cobalamin, is the largest and moststructurally complex of the eight water-soluble B vitamins. Vitamin B₁₂is a class of cobalt and corrin ring molecules that possess vitaminactivity. The sixth coordination site of the corrin ring is either acyano group (—CN), a hydroxyl group (—OH), a methyl group (—CH₃) or a5′-deoxyadenosyl group, creating four forms of vitamin B₁₂, including,cyanocobalamin, hydroxocobalamin, methylcobalamin, andadenosylcobalamin.

Vitamin B₁₂ is synthesized by microbes, but not by humans or plants.Gastrointestinal absorption of vitamin B₁₂, from food or supplements,depends on the presence of sufficient intrinsic factor and calcium ions.Adenosylcobalamin and methylcobalamin are the active forms of vitaminB₁₂ in humans. Vitamin B₁₂ deficiency may result from intrinsic factordeficiency (pernicious anemia), partial or total gastrectomy, ordiseases of the distal ileum, intestinal problems and nerve damage, etc.Conditions that make people vulnerable to vitamin B₁₂ deficiencyinclude: Crohn's disease, multiple sclerosis, HIV/AIDS, advanced age(>65 years), chronic intestinal inflammation, intestinal surgery, foodmoving too quickly through the intestine, strict vegetarian diets,excessive alcohol consumption for longer than 2 weeks, long-term use ofacid reducing drugs, or drug-therapy associated with anemia.

Vitamin B₁₂ has also been used in the treatment of IgE-mediated allergicdiseases, such as allergic rhinitis and asthma. Oral ingested vitaminB₁₂ is ineffective in the treatment of allergic disease, possibly due toliver metabolism.

Cyanocobalamin (Crystamine, Cyomin, Crysti 1000, Nascobal®) is the mostwidely sold analogue of vitamin B₁₂. Cyanocobalamin is available ininjectable (subcutaneous or intramuscular) and oral forms and has theadvantage of having a stable shelf life at standard temperature andpressure (STP). Nascobal®, an intranasal gel formulation ofcyanocobalamin, has been clinically shown to maintain adequate serumlevels of vitamin B₁₂. The nasal gel can be self-administered through anasal delivery system that avoids the discomfort of intramuscularinjections of B₁₂.

Since vitamin B₁₂ is very large, orally ingested cyanocobalamin isimproperly digested and only small amounts of the vitamin get absorbedby the host. The drawback of the injectable form is that it is invasive,expensive, and inconvenient. Hence, there is a need for more effectiveforms of vitamin B₁₂ that can be absorbed more easily to ameliorateconditions associated with vitamin B₁₂ deficiency.

SUMMARY OF THE INVENTION

Many patients require vitamin B₁₂ supplementation to combat vitamin B₁₂deficiency associated with anemia, pernicious anemia, immune systemdisorders, nerve damage, partial removal of the stomach or smallintestine, or administration of drugs known to impair vitamin B₁₂absorption. Because of the large size of vitamin B₁₂, the body neitherefficiently metabolizes nor absorbs the vitamin. Existing vitamin B₁₂compositions fail to provide convenient self-administration for patientsin a readily absorbable form. These patients often rely onprofessionally administered vitamin B₁₂ injections, which are invasive,painful, expensive, and inconvenient. Accordingly, provided herein arecompositions, methods, and kits that offer superior absorbability andadministration compared to currently available vitamin B₁₂ treatments.

Disclosed herein, in certain embodiments, are compositions, comprising:(a) cyanocobalamin, hydroxocobalamin, methylcobalamin in substantiallyequivalent ratios; and (b) a carrier suitable for forming a solid orsemi-solid carrier matrix. In some embodiments, the carrier is a sugar,sugar alcohol, polyethylene glycol (PEG), starch, gum, polymer, orcombination thereof. In some embodiments, the carrier comprises isomalt,a PEG, or a combination thereof. In some embodiments, the PEG isPEG-8000. In some embodiments, the carrier comprises PEG-8000, andisomalt, or a derivative thereof. In some embodiments, the compositionsfurther comprise a lubricant. In some embodiments, the lubricant ismagnesium stearate. In some embodiments, the compositions furthercomprise a flavoring agent. In some embodiments, the flavoring agent is:apple, almond, amaretto, anise, apricot, banana, banana orange,blackberry, black cherry, black currant, black walnut, blueberry,brandy, bubblegum, butter rum, butterscotch, caramel, cinnamon, citrus,citrus punch, cherry, chocolate, chocolate banana pie, chocolate coveredcherry, chocolate hazelnut, cloves, coconut, coffee, cotton candy, crèmede menthe, egg nog, English toffee, ginger, grape, grapeade, grapebubblegum, grapefruit, fig, hazelnut, honey, Irish cream, kiwi,lavender, lemon, licorice, lime, maple, marshmallow, mint, mocha,molasses, orange, orange cream, passion fruit, peach, pecan, peppermint,pina colada, pineapple, pistachio, plum, praline, pomegranate, pumpkin,raspberry, red licorice, root beer, sassafras, sour apple, spearmint,strawberry, strawberry cream, tangerine, tropical fruit, tutti-fruiti,vanilla, walnut, watermelon, white chocolate, wild cherry, orwintergreen. In some embodiments, the flavoring agent is cherry. In someembodiments, the composition is formulated as a lozenge, a candy, awafer, a tablet, a patch, a film, a spray, a lip balm, or gum. In someembodiments, the composition is formulated as a lozenge. In someembodiments, the cyanocobalamin, hydroxocobalamin, and methylcobalamin,together, comprise about 1.2% wt/wt of the composition. In someembodiments, the compositions comprise substantially equivalent ratiosof cyanocobalamin, hydroxocobalamin, and methylcobalamin, as well asisomalt, polyethylene glycol, flavoring, and magnesium stearate.

Disclosed herein, in certain embodiments, is a method for treating orameliorating vitamin B₁₂ deficiency in a human in need thereof,comprising: administering to the human a composition comprising (a)methylcobalamin, hydroxocobalamin, and cyanocobalamin in substantiallyequivalent ratios, (b) a carrier suitable for forming solid orsemi-solid carrier matrix, (c) a flavoring agent, and optionally, (d) alubricant. In some embodiments, the composition comprises: (a)methylcobalamin, hydroxocobalamin, and cyanocobalamin in substantiallyequivalent ratios, (b) isomalt, (c) PEG, (d) cherry flavoring, and,optionally, (e) magnesium stearate. In some embodiments, the compositioncomprises: (a) methylcobalamin, hydroxocobalamin, and cyanocobalamin insubstantially equivalent ratios, (b) isomalt, (c) PEG, (d) cherryflavoring, and (e) magnesium stearate. In some embodiments, the vitaminB₁₂ deficiency is associated with anemia. In some embodiments, thevitamin B₁₂ deficiency is associated with pernicious anemia. In someembodiments, the vitamin B₁₂ deficiency is associated with: Graves'disease, hypothyroidism, thyroiditis, vitiligo, Addison's disease,atrophic gastritis, and/or thrombocytopenia. In some embodiments, thevitamin B₁₂ deficiency is associated with: amyotrophic lateral sclerosis(ALS), multiple sclerosis (MS), Crohn's disease, Celiac disease,ulcerative colitis, Alzheimer's disease, HIV/AIDS, joint inflammation,and/or arthritis. In some embodiments, the vitamin B₁₂ deficiency isassociated with the administration of drugs known to impair absorptionof vitamin B₁₂. In some embodiments, the drug known to impair absorptionof vitamin B₁₂ is: a gastric acid inhibitor, a biguanide, a proton pumpinhibitor, an H₂ receptor antagonist, metformin, and/or chloramphenicol.

In some embodiments, the drug known to impair absorption of vitamin B₁₂is methotrexate. In some embodiments, the vitamin B₁₂ deficiency isassociated with ataxia. In some embodiments, the vitamin B₁₂ deficiencyis associated with partial removal of the stomach or small intestine. Insome embodiments, the vitamin B₁₂ deficiency is associated withalcoholism. In some embodiments, the hereditary disorder is selectedfrom: Alagille's syndrome, severe methylenetetrahydrofolate reductasedeficiency, homocystinuria, and/or transcobalamin deficiency.

Disclosed herein, in certain embodiments, is a kit, comprising: acomposition comprising (a) methylcobalamin, hydroxocobalamin, andcyanocobalamin in substantially equivalent ratios, (b) a carriersuitable for forming solid or semi-solid carrier matrix, (c) a flavoringagent, and optionally, (d) a lubricant. In some embodiments, thecomposition comprises: (a) methylcobalamin, hydroxocobalamin, andcyanocobalamin in substantially equivalent ratios, (b) isomalt, (c) PEG,(d) cherry flavoring, and, optionally, (e) magnesium stearate. In someembodiments, the composition comprises: (a) methylcobalamin,hydroxocobalamin, and cyanocobalamin in substantially equivalent ratios,(b) isomalt, (c) PEG, (d) cherry flavoring, and (e) magnesium stearate.In some embodiments, the kit further comprises instructions for use.

DETAILED DESCRIPTION OF THE INVENTION

Existing vitamin B₁₂ compositions fail to provide users with acomposition that provides an adequate absorption profile in aconveniently self-administered medium.

Advantages of the compositions, methods, and kits described hereininclude, but are not limited to, providing a non-invasive medium forvitamin B₁₂ self-administration. Additional advantages of thecompositions, methods, and kits described herein include, providing alower cost alternative to traditional vitamin B₁₂ administration.

Described herein, in certain embodiments is a composition, comprising:cyanocobalamin, hydroxocobalamin and methylcobalamin in substantiallyequivalent ratios.

Also described herein in certain embodiments, is a method for treatingor ameliorating a disease associated with vitamin B₁₂ deficiency,comprising: administering the composition described herein.

Also described herein in certain embodiments, is a kit, comprising: thecomposition described herein and instructions for use.

Certain Definitions

The following terms used in the specification and claims shall have thefollowing meanings for the purpose of the Application. Unless otherwisedefined, all technical terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisinvention belongs.

As used in this specification and the appended claims, the singularforms “a,” “an,” and “the” include plural references unless the contextclearly dictates otherwise. Any reference to “or” herein is intended toencompass “and/or” unless otherwise stated.

The term “active ingredients or compounds” of the invention refers tocobalamins including, but not limited to, adenosylcobalamin,cyanocobalamin, methylcobalamin, hydroxocobalamin, etc. The activeingredients are used in different mixtures containing varying effectiveamounts of each active compound of the invention, which would besuitable for the treatment of different types of vitamin B₁₂deficiencies.

The term “mixture” refers to a combination containing different types ofactive ingredients defined above, in effective amounts, useful for thetreatment of vitamin B₁₂ deficiency.

The term “effective amount” refers to that amount, which whenadministered, either alone or in a mixture, is sufficient to effect thetreatment of a condition with vitamin B₁₂ deficiency.

The term “inert ingredients” refers to components like pharmaceuticallyacceptable carriers, adjuvant, diluents or excipients, etc., that mustbe compatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

The term “composition” or a “formulation” as used herein refers to aproduct comprising the specified active ingredients in the specifiedamounts, as well as any product which results, directly or indirectly,from the combination of the specified active ingredients in thespecified amounts. Such term is intended to encompass a productcomprising the active ingredient(s), and the inert ingredient(s) thatmake up the carrier, as well as any product which results, directly orindirectly, from combination, complexation, or aggregation of any two ormore of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by mixing anyactive compound of the present invention and a pharmaceuticallyacceptable carrier.

The phrase “substantially equivalent ratio” means the ratio of onecomponent to another component (for example, the ratio ofmethylcobalamine to hydroxycobalamin to cyanocobalamin) is the same,plus or minus about 30%, about 25%, about 20%, about 15%, about 10%,about 5%, about 2.5%, about 1%.

The terms “administration of” and/or “administering a” compositionrefers to providing any composition of the invention, in anyformulation, to a human in need of treatment.

The term “buccal” refers to delivery of a drug by passage of the drugthrough the buccal mucosa into the blood stream.

As used herein, “buccal mucosa” refers to the epithelial membraneslining the mouth, including the cheek and under the tongue (sublingual).

Compositions

Disclosed herein, in certain embodiments, are compositions, comprising:cyanocobalamin, hydroxocobalamin, and methylcobalamin in substantiallyequivalent ratios. In some embodiments, the composition furthercomprises a carrier suitable for forming solid or semi-solid carriermatrix. In other embodiments, the composition also comprises alubricant. In some embodiments, the composition further comprises aflavoring agent.

In some embodiments, the composition comprises a carrier suitable forforming solid or semi-solid carrier matrix. In some embodiments, thecarrier is selected from water, sugar or sugar substitutes, sugaralcohol, polyethylene glycol, alcohols, glycerin, oils or phospholipids,proteins, waxes, gums, or polymers.

Examples of suitable sugars include, but are not limited to, granulatedsugar, powdered sugar, isomaltulose, lactosucrose, corn syrup, cornsyrup solids, high fructose corn syrup, honey, maple syrup,maltodextrin, crystalline-fructose, dextrose, nonpareils, stevia sugar,acesulfame K, aspartame, neotame, saccharin, sucralose, trehalose,tagatose, fructo-oligosaccaride, derivatives thereof, or anycombinations thereof.

Examples of suitable sugar alcohols include, but are not limited to,sorbitol, xylitol, maltitol, isomalt, lactitol, mannitol, erythritol,hydrogenated starch hydrosates, derivatives thereof, or any combinationsthereof. In some embodiments, the carrier comprises isomalt or aderivative thereof. Exemplary isomalt derivatives include, but are notlimited to, galenIQ™ 720, galenIQ™ 721, galenIQ™ 800/810, galenIQ™960/980, galenIQ™ 981, and galenIQ™ 990.

Examples of suitable polyethylene glycols (PEGs) include, but are notlimited to, PEGs with molecular weights between 900 and 8500, includingPEG-1000, -1450, -1500, -2000, -3000, -4000, -5000, -6000, -7000, -8000,derivatives thereof, or any combinations thereof. In some embodiments,the carrier comprises PEG-8000.

Examples of suitable oils and phospholipids include, but are not limitedto, mineral oil, essential oil, castor oil, fatty acids, vegetable oils,sweet almond oil, apricot kernel oil, avocado oil, grapeseed oil, hempseed oil, macadamia oil, olive oil, and sunflower oil, coconut oil, palmoil, mango butter, and shea butter, purified egg or soya lecithins(lecithin E100, lecithin E80 and phospholipons, for example,phospholipon 90), ceramides, hydrogenated phospholipids,phosphatidylethanolamine, phosphatidylglycerol, phosphotidylcholine,phosphatidylserine, dipalmitoylphosphatidylcholine,dipalmitoylglycerophosphatidylcholine, dimyristoylphosphatidylcholine,distearoylphosphatidylcholine, cardiolipin, phosphatidylinositol,glycerophosphocholine, phosphatidic acid, sphingomyelin, derivativesthereof, or any combinations thereof.

Examples of suitable polysaccharides, including, but are not limited to:hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropylcellulose ethers, hydroxyethyl cellulose, sodium carboxymethylcellulose, croscarmellose sodium, methyl cellulose, ethyl cellulose,microcrystalline cellulose, low-substituted hydroxypropyl cellulose,pullulan, dextran, dextrin, levan, elsinan, chitosan, pectins, starches,cellulose acetate phthalate, cellulose acetate butyrate, amylase starch,hydroxypropylated high amylase starch, sodium alginate, alginic acid,carboxymethyl cellulose, derivatives thereof, or any combinationsthereof.

Examples of suitable proteins include, but are not limited to, collagen,zein, soy protein isolate, whey protein isolate, gluten, casein,gelatin, derivatives thereof, or any combinations thereof.

Examples of suitable waxes, include, but are not limited to: lanolin,beeswax, candelilla wax, carnuba wax, rice wax, ouricurry wax, espartograss wax, cork fibre wax, sugarcane wax, microcrystalline waxes,paraffins and ozokerite, polyethylene waxes, olefin wax,silicone-modified olefin wax, derivatives thereof, or any combinationsthereof.

Examples of suitable gums, include, but are not limited to: xanthan gum,tragacanth gum, acacia gum, arabic gum, gellan gum, carrageenan, locustbean gum, guar gum, derivatives thereof, or any combinations thereof.

Examples of suitable polymers, include, but are not limited to: vinylpolymers and copolymers, acrylic acid polymers and copolymers,polyethylene oxides, polyacrylates, polyvinylpyrrolidone, polyvinylalcohol, HPMC K15, 5-methyl-pyrrolidinone chitosan, derivatives thereof,or any combinations thereof.

Exemplary additional carriers that may be used with the compositionsdisclosed herein include, but are not limited to, glycerin, silicone,petroleum jelly, petrolatum, parabens, derivatives thereof, or anycombinations thereof.

In some embodiments, the carrier comprises an isomalt and PEG-8000.

In some embodiments, the lubricant is selected from: magnesium stearate,calcium stearate, stearic acid, sodium stearylfumarate, talc,hydrogenated vegetable oils and polyethylene glycol. In someembodiments, the lubricant is magnesium stearate.

In some embodiments, the flavoring agent is selected from: syntheticflavor oils and flavoring aromatics and/or oils, oleoresins and extractsderived from plants, leaves, flowers, fruits, and so forth, andcombinations thereof. Non-limiting representative flavor oils includespearmint oil, cinnamon oil, oil of wintergreen (methyl salicylate),peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, thymeoil, cedar leaf oil, oil of nutmeg, allspice, oil of sage, mace, oil ofbitter almonds, and cassia oil. Also useful flavorings are artificial,natural and synthetic fruit flavors such as vanilla, and citrus oilsincluding lemon, orange, lime, grapefruit, and fruit essences includingapple, pear, peach, grape, strawberry, raspberry, cherry, plum,pineapple, apricot and so forth. These flavoring agents may be used inliquid or solid form and may be used individually or in admixture.Commonly used flavors include mints such as peppermint, menthol,artificial vanilla, cinnamon derivatives, and various fruit flavors,whether employed individually or in admixture. Other useful flavoringsinclude aldehydes and esters such as cinnamyl acetate, cinnamaldehyde,citral diethylacetal, dihydrocarvyl acetate, eugenyl formate,p-methylamisol, and so forth may be used. Generally any flavoring orfood additive such as those described in Chemicals Used in FoodProcessing, publication 1274, pages 63-258, by the National Academy ofSciences, may be used.

Further examples of aldehyde flavorings include but are not limited toacetaldehyde (apple), benzaldehyde (cherry, almond), anisic aldehyde(licorice, anise), cinnamic aldehyde (cinnamon), citral, i.e.,alpha-citral (lemon, lime), neral, i.e., beta-citral (lemon, lime),decanal (orange, lemon), ethyl vanillin (vanilla, cream), heliotrope,i.e., piperonal (vanilla, cream), vanillin (vanilla, cream), alpha-amylcinnamaldehyde (spicy fruity flavors), butyraldehyde (butter, cheese),valeraldehyde (butter, cheese), citronellal (modifies, many types),decanal (citrus fruits), aldehyde C-8 (citrus fruits), aldehyde C-9(citrus fruits), aldehyde C-12 (citrus fruits), 2-ethyl butyraldehyde(berry fruits), hexenal, i.e., trans-2 (berry fruits), tolyl aldehyde(cherry, almond), veratraldehyde (vanilla), 2,6-dimethyl-5-heptenal,i.e., melonal (melon), 2,6-dimethyloctanal (green fruit), and2-dodecenal (citrus, mandarin), cherry, grape, strawberry shortcake,mixtures thereof and the like.

In some embodiments, the compositions further comprise antimicrobialagents, plasticizing agents, sulfur precipitating agents, salivastimulating agents, cooling agents, surfactants, stabilizing agents,emulsifying agents, thickening agents, binding agents, coloring agents,sweeteners, fragrances, and the like. Exemplarily sulfur precipitatingagents useful in the present invention include metal salts such ascopper salts (e.g., copper gluconate) and zinc salts (e.g., zinc citrateand zinc gluconate). Exemplarily saliva stimulating agents include, butare not limited to food acids such as citric, lactic, malic, succinic,ascorbic, adipic, fumaric and tartaric acids.

The weight ratio of the respective ingredients may be varied whennecessary and will depend upon the effective dose of each ingredient orthe effective dose of the combination of all the active ingredients in aformulation. Generally, an effective dose of each will be used. In aparticularly preferred embodiment, a combination of active ingredientsis used in the composition, for example, methylcobalamin,hydroxocobalamin, and cyanocobalamin. In a preferred embodiment, acombination of active ingredients is used in the composition, forexample, adenosylcobalamin: hydroxocobalamin: cyanocobalamin. Generally,the active ingredients occur as substantially equivalent ratios. In someembodiments, the composition comprises substantially equivalent ratiosof methylcobalamin, hydroxocobalamin, and cyanocobalamin. Alternatively,in some embodiments, the composition comprises substantially equivalentratios of adenosylcobalamin, cyanocobalamin, and hydroxocobalamin. Theamount of adenosylcobalamin and hydroxocobalamin advantageously willgenerally range from 250-750 μg, while the range for cyanocobalamin willgenerally range from 1500-2500 μg in a 3 mg cobalamin formulation. Othercombinations of active ingredients of the present invention are alsopossible as is understood in the art.

In some embodiments, a composition disclosed herein comprises, by way ofnon-limiting example, 0.5%-2.0%, 0.6%-2.0%, 0.7%-2.0%, 0.8%-2.0%,0.9%-2.0%, 1.0-2.0%, 1.1%-2.0%, 1.2%-2.0%, 1.3%-2.0%, 1.4%-2.0%,1.5%-2.0%, 1.6%-2.0%, 1.7%-2.0%, 1.8%-2.0%,1.9%-2.0%, 0.5%-0.6%,0.5%-0.7%, 0.5%-0.8%, 0.5%-0.9%, 0.5%-1.0%, 0.5%, 1.1%,0.5%-1.2%,0.5%-1.3%, 0.5%-1.4%, 0.5%-1.5%, 0.5%-1.6%, 0.5%-1.7%,0.5%-1.8%, or 0.5%-1.9%, weight/weight cobalamins.

In some embodiments, a composition disclosed herein comprises, by way ofnon-limiting examples, 50-99.5%, 55-99.5%, 60-99.5%, 65-99.5%, 70-99.5%,75-99.5%, 80-99.5%, 85-99.5%, 90-99.5%, 91-99.5%, 92-99.5%, 93-99.5%,94-99.5%, 95-99.5%, 96-99.5%, 97-99.5%, 98-99.5%, or 99-99.5%weight/weight carrier.

Disclosed herein, in certain embodiments, are compositions, comprising:(a) methylcobalamin, hydroxocobalamin, and cyanocobalamin insubstantially equivalent ratios, (b) a carrier suitable for formingsolid or semi-solid carrier matrix, (c) a flavoring agent, andoptionally, (d) a lubricant. Further disclosed herein are compositions,comprising: (a) methylcobalamin, hydroxocobalamin, and cyanocobalamin insubstantially equivalent ratios, (b) isomalt, (c) PEG, (d) cherryflavoring, and, optionally, (e) magnesium stearate. Additionallydisclosed herein are compositions, comprising: (a) methylcobalamin,hydroxocobalamin, and cyanocobalamin in substantially equivalent ratios,(b) isomalt, (c) PEG, (d) cherry flavoring, and (e) magnesium stearate.

The skilled artisan will appreciate that the combination of activeingredients found in the compositions described above also may beadministered separately. In addition, the administration of one elementmay be prior to, concurrent to, or subsequent to the administration ofother element(s).

Further, compositions of the present invention may be used incombination with other drugs that are used in thetreatment/prevention/suppression or amelioration of vitamin B₁₂deficiencies or conditions. Such other drugs may be administered, by aroute and in an amount commonly used therefore, contemporaneously orsequentially with a composition of the present invention. When acomposition of the present invention is used contemporaneously with oneor more other drugs or herbal supplements, vitamin supplements, etc., apharmaceutical composition containing such other drugs in addition tothe composition of the present invention is preferred. Accordingly, thepharmaceutical compositions of the present invention include those thatalso contain one or more other active ingredients, in addition to thecompositions of the present invention.

Formulations

Disclosed herein in certain embodiments, are compositions, comprising:methylcobalamin, hydroxocobalamin, and cyanocobalamin in substantiallyequivalent ratios. In some embodiments, the composition furthercomprises a carrier suitable for forming solid or semi-solid carriermatrix. In other embodiments, the composition also comprises alubricant. In some embodiments, the composition further comprises aflavoring agent. In some embodiments, the compositions are formulatedfor oral administration.

Disclosed herein, in certain embodiments, are compositions, comprising:(a) methylcobalamin, hydroxocobalamin, and cyanocobalamin insubstantially equivalent ratios, (b) a carrier suitable for formingsolid or semi-solid carrier matrix, (c) a flavoring agent, andoptionally, (d) a lubricant; wherein the composition is formulated fororal and/or transmucosal administration. Further disclosed herein arecompositions, comprising: (a) methylcobalamin, hydroxocobalamin, andcyanocobalamin in substantially equivalent ratios, (b) isomalt, (c) PEG,(d) cherry flavoring, and, optionally, (e) magnesium stearate; whereinthe composition is formulated for oral and/or transmucosaladministration. Additionally disclosed herein are compositions,comprising: (a) methylcobalamin, hydroxocobalamin, and cyanocobalamin insubstantially equivalent ratios, (b) isomalt, (c) PEG, (d) cherryflavoring, and (e) magnesium stearate; wherein the composition isformulated for oral and/or transmucosal administration.

It is the primary object of the present invention to providepatient-friendly modes of delivery to patients of such effective amountsof vitamin B₁₂ analogues without the inconvenience and discomfort ofsubcutaneous and intramuscular injections. In accordance with theinvention, vitamin B₁₂ is instilled in a carrier matrix, such ascontrolled-release lozenges, troches, tablets, hard or soft capsules,syrups or elixirs, pressed pills, gel caps, chewing gum, gels such asmetered gels that can be administered intranasally, nasal drops, creams,lotions, aqueous or oily suspensions, dispersible powders or granules,emulsions, sprays or aerosols using flowing propellants, like liposomalsprays, nasal sprays, etc., douches and suppositories, transdermalpatches, etc., all for patient-friendly, self-administration ofeffective amounts of vitamin B₁₂. The invention thereby minimizesinconvenience and discomfort for the patient and alleviates the burdenand time demands imposed on medical staff. In some embodiments, thecompositions disclosed herein are formulated for transdermaladministration. In some embodiments, the compositions are formulated aslozenges, candies, tablets, wafers, films, sprays, gums, lip balms, orpatches. The vitamin B₁₂ in formulations such as lozenges, troches,tablets, hard or soft capsules, gums, film, wafers, sprays, patches andlip balms, etc., are preferably absorbed directly via the mucosa, suchas buccal, nasal mucosa, into the blood stream before being subjected todigestion and degradation in the liver. Preferred vitamin B₁₂formulations include nasal gels, lozenges, including sublinguallozenges, nasal drops, nasal or pulmonary or other mucosal sprays,including liposomal sprays, fast absorbing capsules or tablets, gums,films, wafers, patches and lip balms.

Thus, the vitamin B₁₂ formulations of the present invention may beadministered, but are not limited to, oral, parenteral (e.g.,intramuscular, intraperitoneal, intravenous, ICV, intracisternalinjection or infusion, subcutaneous injection, or implant), byinhalation spray, intranasal, transbuccal, mucosal, pulmonary,transdermal, liposomal, vaginal, rectal, sublingual, or topical routesof administration and may be formulated, alone or together, in suitabledosage unit formulations containing conventional non-toxicpharmaceutically acceptable carriers, adjuvants and vehicles appropriatefor each route of administration.

The pharmaceutical compositions for the administration of thecompositions of this invention may conveniently be presented in dosageunit form and may be prepared by methods well known in the art ofpharmacy. Suitable methods are described in, for example, Remington: TheScience and Practice of Pharmacy, ed. Gennaro et al., 20th Ed. (2000),although the skilled artisan will recognize that other methods are knownand are suitable for preparing the compositions of the presentinvention. All methods include the step of bringing the activeingredient into association with the carrier which constitutes one ormore accessory ingredients. In general, the pharmaceutical compositionsare prepared by uniformly and intimately bringing the active ingredientinto association with a liquid carrier or a finely divided solid carrieror both, and then, if necessary, shaping the product into the desiredformulation. In the pharmaceutical composition the active ingredient isincluded in an effective amount, discussed above, sufficient to producethe desired effect upon the process or condition of diseases.

Tablets

In some embodiments, the compositions disclosed herein are formulated astablets, e.g., fast dissolving tablets.

In some embodiments, the tablet is formulated to dissolve in 1 second to30 minutes, 1 second to 25 minutes, 1 second to 20 minutes, 1 second to15 minutes, 1 second to 14 minutes, 1 second to 13 minutes, 1 second to12 minutes, 1 second to 11 minutes, 1 second to 10 minutes, 1 second to9 minutes, 1 second to 8 minutes, 1 second to 7 minutes, 1 second to 6minutes, 1 second to 5 minutes, 1 second to 4 minutes, 1 second to 3minutes, 1 second to 2 minutes, 1 second to 1 minute, or 1 second to 30seconds.

Tablets contain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid;

binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the techniques described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release.

Capsules

In some embodiments, the compositions disclosed herein are formulated ascapsules, e.g., hard capsules or soft capsules.

In some embodiments, the capsule is formulated to dissolve in 1 secondto 30 minutes, 1 second to 25 minutes, 1 second to 20 minutes, 1 secondto 15 minutes, 1 second to 14 minutes, 1 second to 13 minutes, 1 secondto 12 minutes, 1 second to 11 minutes, 1 second to 10 minutes, 1 secondto 9 minutes, 1 second to 8 minutes, 1 second to 7 minutes, 1 second to6 minutes, 1 second to 5 minutes, 1 second to 4 minutes, 1 second to 3minutes, 1 second to 2 minutes, 1 second to 1 minute, or 1 second to 30seconds.

Wherein the composition is formulated as a hard capsule, in someembodiments, the composition is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin. Where thecomposition is formulated as a soft capsule, in some embodiments, thecomposition is mixed with water or an oil medium, for example peanutoil, liquid paraffin, or olive oil.

Lozenge

In some embodiments, the compositions disclosed herein are formulated aslozenges. In some embodiments, the lozenges may include hard lozenges,soft lozenges, gummy lozenges, or chewable lozenges.

In some embodiments, the lozenge is formulated to dissolve in 1 secondto 30 minutes, 1 second to 25 minutes, 1 second to 20 minutes, 1 secondto 15 minutes, 1 second to 14 minutes, 1 second to 13 minutes, 1 secondto 12 minutes, 1 second to 11 minutes, 1 second to 10 minutes, 1 secondto 9 minutes, 1 second to 8 minutes, 1 second to 7 minutes, 1 second to6 minutes, 1 second to 5 minutes, 1 second to 4 minutes, 1 second to 3minutes, 1 second to 2 minutes, 1 second to 1 minute, or 1 second to 30seconds.

Candy

In some embodiments, the compositions disclosed herein are formulated ascandies. In some embodiments, the candy may include hard candy, softcandy, gummy candy, or chewy candy.

In some embodiments, the candy is formulated to dissolve in 1 second to30 minutes, 1 second to 25 minutes, 1 second to 20 minutes, 1 second to15 minutes, 1 second to 14 minutes, 1 second to 13 minutes, 1 second to12 minutes, 1 second to 11 minutes, 1 second to 10 minutes, 1 second to9 minutes, 1 second to 8 minutes, 1 second to 7 minutes, 1 second to 6minutes, 1 second to 5 minutes, 1 second to 4 minutes, 1 second to 3minutes, 1 second to 2 minutes, 1 second to 1 minute, or 1 second to 30seconds.

Film

In some embodiments, the compositions disclosed herein are formulated asfilms, e.g., dissolvable films. The film, by way of non-limitingexample, is a clear or opaque, flexible, thin material.

The film-forming carrier used in the film formulations is selected fromthe group consisting of pullulan, hydroxypropylmethyl cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone,carboxymethyl cellulose, polyvinyl alcohol, sodium alginate,polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum,arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxyvinylpolymer, amylose, high amylose starch, hydroxypropylated high amylosestarch, dextrin, pectin, chitin, chitosan, levan, elsinan, collagen,gelatin, zein, gluten, soy protein isolate, whey protein isolate, caseinand mixtures thereof.

In some embodiments, the film is formulated to dissolve in 1 second to30 minutes, 1 second to 25 minutes, 1 second to 20 minutes, 1 second to15 minutes, 1 second to 14 minutes, 1 second to 13 minutes, 1 second to12 minutes, 1 second to 11 minutes, 1 second to 10 minutes, 1 second to9 minutes, 1 second to 8 minutes, 1 second to 7 minutes, 1 second to 6minutes, 1 second to 5 minutes, 1 second to 4 minutes, 1 second to 3minutes, 1 second to 2 minutes, 1 second to 1 minute, or 1 second to 30seconds.

Gums

In some embodiments, the compositions disclosed herein are formulated asgums. In some embodiments, the gum may be non degradable chewing gum,degradable chewing gum, or liquid filled chewing gum.

In some embodiments, the gum formulations further comprise natural andsynthetic elastomers and rubbers. For example, carriers suitable for agum formulation include, but are not limited to, substances of vegetableorigin such as chicle, jelutong, gutta percha and crown gum. Syntheticelastomers such as butadiene-styrene copolymers, isobutylene-isoprenecopolymers, polyethylene, polyisobutylene and polyvinyl-acetate andmixtures thereof, are also useful.

In some embodiments, the elastomer solvent comprises methyl, glycerol orpentaerythritol esters of rosins or modified rosins, such ashydrogenated, dimerized or polymerized rosins, or mixtures thereof.Examples of elastomer solvents suitable for use herein include thepentaerythritol ester of partially hydrogenated wood rosin and partiallyhydrogenated wood rosin, pentaerythritol ester of wood rosin, glycerolester of wood rosin, glycerol ester of partially dimerized rosin,glycerol ester of polymerized rosin, glycerol ester of tall oil rosin,glycerol ester of wood rosin and partially hydrogenated wood rosin andthe partially hydrogenated methyl ester of rosin, such as polymers ofalpha-pinene or beta-pinene, terpene resins including polyterpene andmixtures thereof.

A variety of traditional ingredients such as plasticizers or softenerssuch as lanolin, stearic acid, sodium stearate, potassium stearate,glyceryl triacetate, glycerine and the like, for example, natural waxes,petroleum waxes such as polyurethene waxes, paraffin waxes andmicrocrystalline waxes may also be incorporated into the gumformulations disclosed herein to obtain a variety of desirable texturesand consistency properties.

Lip Balm

In some embodiments, the compositions disclosed herein are formulated aslip balms. In some embodiments, the lip balm may be in a tube, stick, orpot.

In some embodiments, the lip balm formulations further comprise a wax orother pharmaceutically acceptable vehicle, emollients, and oils.

Suitable waxes include animal waxes, plant waxes, mineral waxes,silicone waxes synthetic waxes and petroleum waxes. Exemplary specificwaxes include, but are not limited to, carnauba wax; paraffin wax; whitewax; candelilla wax; beeswax; jojoba wax; ozokerite; polyethylene; andcombinations thereof.

In some embodiments, the lip balm formulations further comprise an oilor a butter, e.g., sunflower oil, coconut oil, castor oil, vegetableoil, corn oil, aloe vera oil, canola oil, soybean oil, jojoba oil, oliveoil, babassu oil, avocado oil, apricot oil, meadowfoam seed oil,macademia seed oil, oat kernel oil, palm seed oil, safflower oil,sandalwood oil, sesame oil, almond oil, wheat germ oil, cranberry oil,mango seed butter, raspberry butter, avocado butter, shea butter, olivebutter, kuku butter, monoi butter, peach butter, pistachio butter,coconut butter, cocoa butter, pomegranate butter, rose hip butter,sunflower butter, wheat germ butter, apricot butter, babassu butter,cupuacu butter, kokum butter, hazelnut butter, jojoba butter, sesamebutter, soy butter, almond butter, meadowfoam seed butter, black currentseed butter and cranberry butter.

Buccal Patch

In some embodiments, the compositions disclosed herein are formulated asbuccal patches. In some embodiments, the buccal patch, by way ofnon-limiting example, is a clear or opaque, flexible, thin material.

In some embodiments, the buccal patch is fabricated to dissolvegradually over a predetermined time period. In some embodiments, thebuccal patch further comprises a bioerodible polymeric carrier, and anyexcipients that may be desired, e.g., penetration enhancers. As usedherein, “bioerodible”, i.e., the polymer hydrolyzes at a predeterminedrate upon contact with moisture.

In some embodiments, the bioerodible polymeric carrier comprises apolymer having sufficient tack such that the patch adheres to the buccalmucosa for the time period necessary to produce the desired drug releaseprofile. Generally, the polymeric carriers comprise hydrophilic (watersoluble and water-swellable) polymers that adhere to the wet surface ofthe buccal mucosa. Examples of polymeric carriers useful herein includeacrylic acid polymers and copolymers, e.g., those known as “carbomers”for example, Carbopol®. Other suitable polymers include, but are notlimited to, hydrolyzed polyvinyl alcohol, polyethylene oxides (e.g.,Sentry Polyox®), polyacrylates (e.g, Gantrez®), vinyl polymers andcopolymers, polyvinylpyrrolidone, dextran, guar gum, pectins, starches,and cellulosic polymers such as hydroxypropyl methylcellulose (e.g.,Methocel®), hydroxypropyl cellulose (e.g., Kluce®), hydroxypropylcellulose; ethers, hydroxyethyl cellulose, sodium carboxymethylcellulose, methyl cellulose, ethyl cellulose, cellulose acetatephthalate, cellulose acetate butyrate, and the like.

In some embodiments, the patch is formulated to dissolve in 1 second to30 minutes, 1 second to 25 minutes, 1 second to 20 minutes, 1 second to15 minutes, 1 second to 14 minutes, 1 second to 13 minutes, 1 second to12 minutes, 1 second to 11 minutes, 1 second to 10 minutes, 1 second to9 minutes, 1 second to 8 minutes, 1 second to 7 minutes, 1 second to 6minutes, 1 second to 5 minutes, 1 second to 4 minutes, 1 second to 3minutes, 1 second to 2 minutes, 1 second to 1 minute, or 1 second to 30seconds.

Sprays

In some embodiments, the compositions disclosed herein are formulated assprays. In some embodiments, the compositions disclosed herein areformulated as liposomal sprays. A liposome used for the preparation ofthe liposomal spray comprises of two lipid layers. The lipid layer maybe a monolayer, or may be multilameliar and include multiple layers. Insome embodiments, the liposome comprises phosphatidylcholine, but caninclude various natural (e.g., tissue derived L-oc-phosphatidyl: eggyolk, heart, brain, liver, soybean) and/or synthetic (e.g., saturatedand unsaturated 1,2-diacyl-SN-glycero-3 15 phosphocholines,1-acyl-2-acyl-SN-glycero-3-phosphocholines, 1,2diheptanoyl-SN-glycero-3-phosphocholine) derivatives of the same. Suchlipids can be used alone, or in combination with a helper lipid.Preferred helper lipids are non-ionic or uncharged at physiological pH.Non-ionic lipids include, but are not limited to, cholesterol and DOPE(1,2-dioleolylglyceryl 20 phosphatidylethanolamine). Phosphatidic acid,which imparts an electric charge, may also be added.

In some embodiments, the spray is delivered by a metered dose pump. Inother embodiments, the spray is delivered by mist spray pumps or squeezebottles.

Miscellaneous

Formulations are also useful as dry powders or granules. Dispersible,dry powders are useful for inhalation after aerosolization with asuitable dispersion device. Dry powder dispersion devices formedicaments are described in a number of patent documents. U.S. Pat. No.3,921,637 describes a manual pump with needles for piercing through asingle capsule of powdered medicine. The use of multiple receptacledisks or strips of medication is described in EP 467172 (where areciprocatable piercing mechanism is used to pierce through opposedsurfaces of a blister pack); WO91/02558; WO93/09832; WO94/08522; U.S.Pat. Nos. 4,627,432; 4,811,731; 5,035,237; 5,048,514; 4,446,862; and3,425,600. Other patents which show puncturing of single medicationcapsules include U.S. Pat. Nos. 4,338,931; 3,991,761; 4,249,526;4,069,819; 4,995,385; 4,889,114; and 4,884,565; and EP 469814.WO90/07351 describes a hand-held pump device with a loose powderreservoir. Further dry powder dispensers are also covered in U.S. Pat.No. 6,089,228 which specifically provides an improved apparatus foraerosolizing a powdered medicament, hereby incorporated by reference.

Dispersible powders and granules are also suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present. Syrups and elixirs may beformulated with sweetening agents, for example glycerol, propyleneglycol, sorbitol or sucrose. Such formulations may also contain ademulcent, preservative, flavoring and coloring agent.

The pharmaceutical compositions may sometimes be in the form of asterile injectable aqueous or oleagenous suspension. This suspension maybe formulated according to the known art using those suitable dispersingor wetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compositions of the present invention may also be administered inthe form of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

For topical use, creams, gels including nasal gels, ointments, jellies,solutions or suspensions, mouth washes and gargles, etc., containing thecompositions of the present invention, are employed.

Disorders and Conditions Related to Vitamin B₁₂ Deficiency

Disclosed herein in certain embodiments, are compositions, comprising:methylcobalamin, hydroxocobalamin, and cyanocobalamin in substantiallyequivalent ratios. In some embodiments, the composition furthercomprises a carrier suitable for forming a solid or semi-solid carriermatrix. In other embodiments, the composition also comprises alubricant. In some embodiments, the composition further comprises aflavoring agent. In some embodiments, the compositions are formulatedfor oral administration.

Disclosed herein, in certain embodiments, are compositions, comprising:(a) methylcobalamin, hydroxocobalamin, and cyanocobalamin insubstantially equivalent ratios, (b) a carrier suitable for formingsolid or semi-solid carrier matrix, (c) a flavoring agent, andoptionally, (d) a lubricant; wherein the composition is formulated fororal and/or transmucosal administration. Further disclosed herein arecompositions, comprising: (a) methylcobalamin, hydroxocobalamin, andcyanocobalamin in substantially equivalent ratios, (b) isomalt, (c) PEG,(d) cherry flavoring, and, optionally, (e) magnesium stearate; whereinthe composition is formulated for oral and/or transmucosaladministration. Additionally disclosed herein are compositions,comprising: (a) cyanocobalamin, hydroxocobalamin, and methylcobalamin insubstantially equivalent ratios, (b) isomalt, (c) PEG, (d) cherryflavoring, and (e) magnesium stearate; wherein the composition isformulated for oral and/or transmucosal administration.

The following diseases, disorders and conditions are related to vitaminB₁₂ deficiency, and therefore may be treated, controlled or in somecases prevented, by treatment with the composition of this invention:pernicious anemia; ataxia; autoimmune disorders; patients receiving longterm therapy with gastric acid inhibitors like biguanides; patients withatrophic body gastritis, or who have had partial or total gastrectomy;anemia associated with drug-therapy (for example, methotrexate,metformin, phenobarbital, phenytoin, etc.; alcohol or substance abuse;inflammation of joints; arthritis; burns; neurodegenerative disease likeAlzheimer's disease, amyotrophic lateral sclerosis or multiplesclerosis; senior dementia; allergic diseases such as rhinitis, allergicasthma, etc.; HIV/AIDS where there poor absorption of vitamin B₁₂;irritable bowel syndrome or patients who have undergone intestinalsurgery; inflammatory bowel disease, including Crohn's disease andulcerative colitis; suppression of IgE production; and other disorderswhere vitamin B₁₂ deficiency is a component.

In some embodiments, vitamin B₁₂ deficiency is associated with anemia.In some embodiments, the vitamin B₁₂ deficiency is associated withpernicious anemia. In some embodiments, the vitamin B₁₂ deficiency isassociated with a disease, selected from: Graves' disease,hypothyroidism, thyroiditis, vitiligo, Addison's disease, atrophicgastritis, or thrombocytopenia. In some embodiments, the vitamin B₁₂deficiency is associated with an immune disorder, selected from:amyotrophic lateral sclerosis, multiple sclerosis, Crohn's disease,Celiac disease, ulcerative colitis, Alzheimer's disease, AIDS, jointinflammation, or arthritis. In some embodiments, the vitamin B₁₂deficiency is associated with administration of a drug known to impairabsorption of vitamin B₁₂, wherein the drug known to impair absorptionof vitamin B₁₂ is selected from: gastric acid inhibitors, biguanides,proton pump inhibitors, H₂ receptor antagonists, metformin, orchloramphenicol. In some embodiments, the vitamin B₁₂ deficiency isassociated with ataxia. In some embodiments, the vitamin B₁₂ deficiencyis associated with partial removal of the stomach or small intestine. Insome embodiments, the vitamin B₁₂ deficiency is associated withalcoholism. In some embodiments, the vitamin B₁₂ deficiency isassociated with Alagille's syndrome, severe methylenetetrahydrofolatereductase deficiency, homocystinuria, or transcobalamin deficiency.

Kits

Disclosed herein in certain embodiments, are kits, comprising acomposition comprising: methylcobalamin, hydroxocobalamin, andcyanocobalamin in substantially equivalent ratios. In some embodiments,the composition further comprises a carrier suitable for forming solidor semi-solid carrier matrix. In other embodiments, the composition alsocomprises a lubricant. In some embodiments, the composition furthercomprises a flavoring agent. In some embodiments, the compositions areformulated for oral administration.

Disclosed herein, in certain embodiments, are kits, comprisingcompositions comprising: (a) methylcobalamin, hydroxocobalamin, andcyanocobalamin in substantially equivalent ratios, (b) a carriersuitable for forming solid or semi-solid carrier matrix, (c) a flavoringagent, and optionally, (d) a lubricant; wherein the composition isformulated for oral and/or transmucosal administration. Furtherdisclosed herein are kits, comprising compositions comprising: (a)methylcobalamin, hydroxocobalamin, and cyanocobalamin in substantiallyequivalent ratios, (b) isomalt, (c) PEG, (d) cherry flavoring, and,optionally, (e) magnesium stearate; wherein the composition isformulated for oral and/or transmucosal administration. Additionallydisclosed herein are kits, comprising compositions comprising: (a)methylcobalamin, hydroxocobalamin, and cyanocobalamin in substantiallyequivalent ratios, (b) isomalt, (c) PEG, (d) cherry flavoring, and (e)magnesium stearate; wherein the composition is formulated for oraland/or transmucosal administration.

In certain embodiments, the kits comprise a composition disclosed hereinand instructions for storage, administration, dosing, and disease statefor which the formulation is useful, etc. In yet another embodiment isan article of manufacture comprising a composition or formulationdisclosed herein and an apparatus to dispense or administer theformulation to a given patient, such as a container for housing thecomposition, etc.

In some embodiments, the kits described herein include the compositiondescribed herein, and instructions for using the kit. In furtherembodiments, the kits include packaging materials including, but notlimited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials,containers, bottles, and any packaging material suitable for a selectedformulation and intended mode of administration and treatment, includinglabels listing contents and/or instructions for use, and packageinserts, with instructions for use. In a further embodiment, a label ison or associated with the container. In yet a further embodiment, alabel is on a container when letters, numbers or other charactersforming the label are attached, molded or etched into the containeritself; a label is associated with a container when it is present withina receptacle or carrier that also holds the container, e.g., as apackage insert. In other embodiments a label is used to indicate thatthe contents are to be used for a specific therapeutic application. Inyet another embodiment, a label also indicates directions for use of thecontents, such as in the methods described herein.

In certain embodiments, the composition is presented in a pack ordispenser device which contains one or more unit dosage forms containinga composition provided herein. In another embodiment, the pack forexample contains metal or plastic foil, such as a blister pack. In afurther embodiment, the pack or dispenser device is accompanied byinstructions for administration. In yet a further embodiment, the packor dispenser is also accompanied with a notice associated with thecontainer in form prescribed by a governmental agency regulating themanufacture, use, or sale of pharmaceuticals, which notice is reflectiveof approval by the agency of the form of the drug for human orveterinary administration. In another embodiment, such notice, forexample, is the labeling approved by the U.S. Food and DrugAdministration for prescription drugs, or the approved product insert.In yet another embodiment, compositions containing a compound disclosedherein formulated in a compatible pharmaceutical carrier are alsoprepared, placed in an appropriate container, and labeled for treatmentof an indicated condition.

EXAMPLES Example 1 Composition

A lozenge is prepared. The components of the composition, and theirrespective amounts, by weight, are listed in Table 1.

TABLE 1 Material Milligram per Unit Dose Cyanocobalamin,Hydroxocobalamin, Equal amounts of each Methylcobalamin IsomaltgalenIQ ™ 721 182.750 Polyethylene Glycol 8000 62.500 Flavoring 0.500Magnesium Searate 1.250

Example 2 Manufacture of Vitamin B₁₂ Composition

About 5 grams of cyanocobalamin, about 5 grams of hydroxycobalaminacetate and about 5 grams of methylcobalamin are passed through a #20mesh stainless steel screen.

About 15 grams of isomalt is passed through a #20 mesh screen andcombined with the methyl-, cyano- and hydroxy-cobalamin mixture.Pre-blend 1 is mixed until a substantially homogenous mixture isobserved.

About 90 grams of isomalt is passed through a #20 mesh screen andcombined with pre-blend 1. Pre-blend 2 is mixed until a substantiallyhomogenous mixture is observed.

About 360 grams of isomalt is passed through a #20 mesh screen andcombined with pre-blend 2. Pre-blend 3 is mixed until a substantiallyhomogenous mixture is observed. Pre-blend 3 is transferred into ablender.

About 448.75 grams of isomalt, about 312.5 grams of PEG-8000 and about2.5 grams of cherry flavoring are passed through a #20 mesh screen andtransferred into the blender with pre-blend 3 and blended untilsubstantially homogenous to generate blend 1.

About 6.250 grams of magnesium stearate is passed through a #20 meshscreen and combined with blend 1 in the blender and blended untilsubstantially homogenous to generate blend 2.

Blend 2 is divided into unit dosages and each unit dosage is compressedinto a tablet.

Example 3 Treating Vitamin B₁₂ Deficiency with Vitamin B₁₂ DescribedHerein

A human presents with vitamin B₁₂ deficiency associated with perniciousanemia, including impaired perception of deep touch and deepmuscle-tendon reflexes. The patient self-administers a vitamin B₁₂lozenge according to Example 1. The human's symptoms of vitamin B₁₂deficiency are decreased.

What is claimed is:
 1. A composition, comprising: a. cyanocobalamin,hydroxocobalamin, methylcobalamin in substantially equivalent ratios;and b. a carrier suitable for forming a solid or semi-solid carriermatrix.
 2. The composition of claim 1, wherein the carrier is a sugar,sugar alcohol, polyethylene glycol, starch, gum, polymer, or combinationthereof.
 3. The composition of claim 2, wherein the sugar alcohol isisomalt or a derivative thereof.
 4. The composition of claim 2, whereinthe PEG is PEG-8000.
 5. The composition of claim 2, wherein the carriercomprises PEG-8000, and isomalt or a derivative thereof.
 6. Thecomposition of claim 1, further comprising a lubricant.
 7. Thecomposition of claim 6, wherein the lubricant is magnesium stearate. 8.The composition of claim 1, further comprising a flavoring agent.
 9. Thecomposition of claim 8, wherein the flavoring agent is cherry.
 10. Thecomposition of claim 1, wherein the composition is formulated as alozenge, a candy, a wafer, a tablet, a patch, a film, a spray, a lipbalm, or gum.
 11. The composition of claim 10, wherein the compositionis formulated as a lozenge.
 12. A method for treating or amelioratingvitamin B₁₂ deficiency in a human in need thereof, comprising:administering to the human the composition of claim
 1. 13. The method ofclaim 12, wherein the vitamin B₁₂ deficiency is associated with anemia,Graves' disease, hypothyroidism, thyroiditis, vitiligo, Addison'sdisease, atrophic gastritis, thrombocytopenia, amyotrophic lateralsclerosis, multiple sclerosis, Crohn's disease, Celiac disease,ulcerative colitis, Alzheimer's disease, AIDS, joint inflammation,arthritis, ataxia, partial removal of the stomach or small intestine,alcoholism, Alagille's syndrome, severe methylenetetrahydrofolatereductase deficiency, homocystinuria, or transcobalamin deficiency, orany combinations thereof.
 14. The method of claim 13, wherein thevitamin B₁₂ deficiency is associated with pernicious anemia.
 15. Themethod of claim 12 wherein the vitamin B₁₂ deficiency is associated withadministration of drugs known to impair absorption of vitamin B₁₂. 16.The method of claim 15, wherein the drug known to impair absorption ofvitamin B₁₂ is: a gastric acid inhibitor, a biguanide, a proton pumpinhibitor, an H₂ receptor antagonist.
 17. The method of claim 15,wherein the drug known to impair absorption of vitamin B₁₂ is:metformin, chloramphenicol, methotrexate, or any combination.
 18. A kitcomprising: the composition of claim
 1. 19. The kit of claim 18, furthercomprising instructions for use.